Friedreich Ataxia
Conditions
Brief summary
The primary objective is to test the safety and tolerability of short-term therapy with a nicotinamide adenine dinucleotide (NAD+) precursor (MIB-626) in adults with Friedreich's Ataxia (FA) without overt heart failure and with a left ventricular ejection fraction ≥ 40%. A key secondary objective is to test the effects of MIB-626 on cardiac and skeletal muscle bioenergetics.
Detailed description
The primary focus for this protocol is safety and tolerability. We will systematically assess for adverse events using a safety monitoring uniform report form. We will also use cardiac 31-Phosphorus-Magnetic Resonance Spectroscopy (MRS) to measure the Phosphocreatine(PCr)/Adenosine triphosphate (ATP)- γ ratio before and after treatment with MIB-626. In addition, if time permits we will use proton (1H)-MRS to measure skeletal muscle nicotinamide adenine dinucleotide (NAD+) before and after treatment.
Interventions
DRUGMIB-626
Two (2) 500 mg Tablets, By Mouth, Daily
Sponsors
Children's Hospital of Philadelphia
Metro International Biotech, LLC
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
OTHER
Masking
NONE
Intervention model description
Open Label, 14 Days (+/- 2 Days)
Eligibility
Sex/Gender
ALL
Age
18 Years to 64 Years
Healthy volunteers
No
Inclusion criteria
* Molecular diagnosis of Friedreich's Ataxia (FA). * Males and females, ages 18 years to \< 65 years.
Exclusion criteria
* Known sensitivity to nicotinamide-containing compounds. * Concurrent use of Vitamin B3 supplements and/or any medications likely to increase risk of MIB-626 toxicity. * HgbA1c \> (great than or equal to) 8.5% and or Diabetes Mellitus (DM) requiring insulin or insulin secretagogue. * Kidney disease (Estimated Glomerular Filtration Rate (eGFR) \< 60 ml/min/1.73 m2) using serum creatinine and MDRD equation. The eGFR levels will be calculated using the Modified Diet in Renal Disease Study (MDRD) equation, which is the equation used by the Children's Hospital Of Philadelphia laboratory. * Liver disease (Aspartate Aminotransferase (AST)/Alanine Aminotransferase (ALT) \> 3 x Upper Limit of Normal) * Severe co-existing cardiac disease (Ejection Fraction (EF) \< 40%, known arrhythmia) as demonstrated by an echocardiogram within 12 months of screening. * Any contraindication to MRI, including spinal rods (related to unknown safety considerations for cardiac 31-Phosphorus -MRS). * Use of any investigational agent within 4 weeks of enrollment. * Females: Pregnant/lactating or planning to become pregnant during their participation. * Any medical condition that, in the opinion of the investigator, will interfere with the safe completion of the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Individuals With Treatment-emergent Adverse Events as Assessed by Common Terminology Criteria for Adverse Events Version 5.0. | 14 Days | Safety will be monitored through collection of laboratory assessments (CBC, complete metabolic profile, lipid profile, HbA1c), vital signs (heart rate, blood pressure), and ECG, all of which will be reviewed for clinically relevant abnormalities, and standardized assessment of symptoms. We report the proportion of individuals who had at least one treatment-emergent adverse event of Grade 1 or higher. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Cardiac 31-Phosphorus-Magnetic Resonance Spectroscopy (MRS): Phosphocreatine (PCr)/Adenosine Tri-Phosphate (ATP) Ratio | Change from baseline to 14 days. | Measure the within-participant change in PCr/ATP ratio before and after treatment with MIB-626. |
| Post-Exercise Creatine Chemical Exchange Saturation Transfer (CrCEST) Magnetic Resonance Imaging (MRI) | Change from baseline to 14 days. | Assess the within-participant change in skeletal muscle post-exercise CrCEST recovery (an index of skeletal muscle mitochondrial oxidative phosphorylation capacity). |
| Grip Strength | Change from baseline to 14 days. | Assess within-participant changes in grip strength (via hand grip dynamometry) before and after treatment with MIB-626. |
| Concentration of Nicotinamide Adenine Dinucleotide (NAD+) in Whole Blood | Change from baseline to 14 days. | Measure the concentration of NAD+ in whole blood before and after treatment with MIB-626. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Open Label - MIB-626 MIB-626
MIB-626: Two (2) 500 mg Tablets, By Mouth, Daily | 7 |
| Total | 7 |
Baseline characteristics
| Characteristic | Open Label - MIB-626 |
|---|---|
| Age, Continuous | 26 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 5 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 7 Participants |
| Sex: Female, Male Female | 2 Participants |
| Sex: Female, Male Male | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 7 |
| other Total, other adverse events | 4 / 7 |
| serious Total, serious adverse events | 0 / 7 |
Outcome results
Primary
Percentage of Individuals With Treatment-emergent Adverse Events as Assessed by Common Terminology Criteria for Adverse Events Version 5.0.
Safety will be monitored through collection of laboratory assessments (CBC, complete metabolic profile, lipid profile, HbA1c), vital signs (heart rate, blood pressure), and ECG, all of which will be reviewed for clinically relevant abnormalities, and standardized assessment of symptoms. We report the proportion of individuals who had at least one treatment-emergent adverse event of Grade 1 or higher.
Time frame: 14 Days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Open Label - MIB-626 | Percentage of Individuals With Treatment-emergent Adverse Events as Assessed by Common Terminology Criteria for Adverse Events Version 5.0. | 4 Participants |
Secondary
Cardiac 31-Phosphorus-Magnetic Resonance Spectroscopy (MRS): Phosphocreatine (PCr)/Adenosine Tri-Phosphate (ATP) Ratio
Measure the within-participant change in PCr/ATP ratio before and after treatment with MIB-626.
Time frame: Change from baseline to 14 days.
Population: 1/7 individuals was unable to complete an MRI scan.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Open Label - MIB-626 | Cardiac 31-Phosphorus-Magnetic Resonance Spectroscopy (MRS): Phosphocreatine (PCr)/Adenosine Tri-Phosphate (ATP) Ratio | -0.445 PCr to ATP ratio |
p-value: 0.18Wilcoxon (Mann-Whitney)
Secondary
Concentration of Nicotinamide Adenine Dinucleotide (NAD+) in Whole Blood
Measure the concentration of NAD+ in whole blood before and after treatment with MIB-626.
Time frame: Change from baseline to 14 days.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Open Label - MIB-626 | Concentration of Nicotinamide Adenine Dinucleotide (NAD+) in Whole Blood | 49.9 micro-molar |
p-value: 0.03Wilcoxon (Mann-Whitney)
Secondary
Grip Strength
Assess within-participant changes in grip strength (via hand grip dynamometry) before and after treatment with MIB-626.
Time frame: Change from baseline to 14 days.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Open Label - MIB-626 | Grip Strength | -0.65 kg |
p-value: 0.21Wilcoxon (Mann-Whitney)
Secondary
Post-Exercise Creatine Chemical Exchange Saturation Transfer (CrCEST) Magnetic Resonance Imaging (MRI)
Assess the within-participant change in skeletal muscle post-exercise CrCEST recovery (an index of skeletal muscle mitochondrial oxidative phosphorylation capacity).
Time frame: Change from baseline to 14 days.
Population: This secondary outcome measure could not be collected for any participant because insufficient MRI scanning time remained during the visits after main outcomes were collected.